Colorectal Cancer: Differential Gene Expression and In Vitro Response to 5-Fluorouracil, Novel Fluoropyrimidine F10, and Potential Synergy with Lupeol

Colorectal cancer (CRC) remains one of the most lethal malignancies in the United States, with African American (AA) patients experiencing disproportionately higher incidence and mortality compared to Caucasian Americans (CAs). These disparities have been linked to tumor-intrinsic genomic differences, including microsatellite instability (MSI) and p53 mutation status, which may influence chemotherapeutic response, particularly to the standard-of-care agent 5-fluorouracil (5-FU). However, mechanistic insights have been limited by the lack of racially diverse preclinical models. Here, we evaluated the efficacy of F10 (a novel fluoropyrimidine polymer) vs. 5-FU using AA- and CA-derived CRC cell lines with distinct MSI and p53 profiles. MTT assays revealed that MSI status, more than racial origin, predicted 5-FU sensitivity. Transcriptomics uncovered distinct gene expression patterns associated with MSI status and racial background, particularly in drug metabolism pathways. F10 demonstrated superior potency and consistency vs. 5-FU across all cell lines, independent of race, MSI, or p53 status. Additionally, in silico docking and immunofluorescence suggest that the dietary triterpene lupeol enhances F10 efficacy, perhaps through stabilization of the Fas apoptosis pathway. These findings underscore the therapeutic potential of F10 and the importance of integrating diverse tumor models with dietary adjuvants to inform more effective and inclusive CRC treatment strategies.